Transdermal administration of nonsteroidal anti-inflammatory drugs using hydroxide-releasing agents as permeation enhancers

ABSTRACT

A method is provided for increasing the permeability of skin or mucosal tissue to transdermally administered nonsteroidal anti-inflammatory drugs (NSAIDs). The method involves use of a specified amount of a hydroxide-releasing agent, the amount optimized to increase the flux of the NSAID through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. Formulations and drug delivery systems for co-administering a hydroxide-releasing agent with an NSAID are provided as well.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. Ser. No. 09/737,830, filed Dec. 14, 2000now U.S. Pat. No. 6,645,520; which is a continuation-in-part of U.S.Ser. No. 09/569,889, filed May 11, 2000 now abandoned; which is acontinuation-in part of U.S. Ser. No. 09/465,098, filed Dec. 16, 1999now abandoned; the disclosures of which are incorporated by reference.

TECHNICAL FIELD

This invention relates generally to transdermal administration ofpharmacologically active agents, and more particularly relates tomethods and compositions for administering nonsteroidalanti-inflammatory drugs (NSAIDs) transdermally.

BACKGROUND

The delivery of drugs through the skin provides many advantages;primarily, such a means of delivery is a comfortable, convenient andnoninvasive way of administering drugs. The variable rates of absorptionand metabolism encountered in oral treatment are avoided, and a highdegree of control over blood concentrations of any particular drug ismade possible. Other inherent inconveniences—e.g., gastrointestinalirritation and the like—are reduced or eliminated as well. This latteradvantage is particularly important with drugs that are known to bequite problematic with respect to gastrointestinal side effects. Oraladministration of nonsteroidal anti inflammatory drugs, or “NSAIDs,” iswell known to result in mild to serious gastrointestinal side effects ina significant fraction of patients receiving the medication.

However, skin is a structurally complex, relatively thick membrane.Molecules moving from the environment into and through intact skin mustfirst penetrate the stratum corneum and any material on its surface.They must then penetrate the viable epidermis, the papillary dermis, andthe capillary walls into the blood stream or lymph channels. To be soabsorbed, molecules must overcome a different resistance to penetrationin each type of tissue. Transport across the skin membrane is thus acomplex phenomenon. However, it is the cells of the stratum corneumwhich present the primary barrier to absorption of topical compositionsor transdermally administered drugs. The stratum corneum is a thin layerof dense, highly keratinized cells approximately 10-15 microns thickover most of the body. It is believed to be the high degree ofkeratinization within these cells as well as their dense packing whichcreates in most cases a substantially impermeable barrier to drugpenetration.

With many drugs, the rate of permeation through the skin is extremelylow. For example, as pointed out in U.S. Pat. No. 5,527,832 to Chi etal., the low percutaneous absorption of typical nonsteroidalanti-inflammatory drugs, i.e., propionic acid derivatives such asketoprofen, ibuprofen, flurbiprofen, naproxen, and the like, isinsufficient to allow transdermal delivery of these drugs attherapeutically effective rates. Consequently, a means for enhancing thepermeability of the skin is desired to effect transport of an NSAID intoand through intact skin.

In order to increase the rate at which a drug penetrates through theskin, various approaches have been followed, each of which involves theuse of either a chemical penetration enhancer or a physical penetrationenhancer. Physical enhancement of skin permeation include, for example,electrophoretic techniques such as iontophoresis. The use of ultrasound(or “phonophoresis”) as a physical penetration enhancer has also beenresearched. Chemical enhancers are compounds that are administered alongwith the drug (or in some cases the skin may be pretreated with achemical enhancer) in order to increase the permeability of the stratumcorneum, and thereby provide for enhanced penetration of the drugthrough the skin. Ideally, such chemical penetration enhancers (or“permeation enhancers,” as the compounds are referred to herein) arecompounds that are innocuous and serve merely to facilitate diffusion ofthe drug through the stratum corneum.

Various compounds for enhancing the permeability of skin are known inthe art and described in the pertinent texts and literature. Compoundsthat have been used to enhance skin permeability include: sulfoxidessuch as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C₁₀MSO);ethers such as diethylene glycol monoethyl ether (available commerciallyas Transcutol®) and diethylene glycol monomethyl ether; surfactants suchas sodium laurate, sodium lauryl sulfate, cetyltrimethylammoniumbromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20,40, 60, 80) and lecithin (U.S. Pat. No. 4,783,450); the 1-substitutedazacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one(available under the trademark Azone® from Nelson Research & DevelopmentCo., Irvine, Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616and 4,557,934); alcohols such as ethanol, propanol, octanol, benzylalcohol, and the like; fatty acids such as lauric acid, oleic acid andvaleric acid; fatty acid esters such as isopropyl myristate, isopropylpalmitate, methylpropionate, and ethyl oleate; polyols and estersthereof such as propylene glycol, ethylene glycol, glycerol, butanediol,polyethylene glycol, and polyethylene glycol monolaurate (PEGML; see,e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compoundssuch as urea, dimethylacetamide (DMA), dimethylformamide (DMF),2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; organic acids, particularlysalicylic acid and salicylates, citric acid and succinic acid; andcertain peptides, e.g., peptides having Pro-Leu at the N-terminus andfollowed by a protective group (see U.S. Pat. No. 5,534,496).Percutaneous Penetration Enhancers, eds. Smith et al. (CRC Press, 1995)provides an excellent overview of the field and further backgroundinformation on a number of chemical and physical enhancers.

Although many chemical permeation enhancers are known, there is anongoing need for enhancers that are highly effective in increasing therate at which a pharmacologically active agent, particularly an NSAID,permeates through the skin, do not result in skin damage, irritation,sensitization, or the like. In particular, there is a need for chemicalpermeation enhancers that enable the effective transdermaladministration of NSAIDs, “effective” administration meaning that theflux of drug through the skin is such that therapeutically effectiveblood levels are achieved. It has now been discovered thathydroxide-releasing agents are highly effective permeation enhancers,even when used without co-enhancers, and provide all of theaforementioned advantages relative to known permeation enhancers.Furthermore, in contrast to conventional enhancers, transdermaladministration of drugs with hydroxide-releasing agents as permeationenhancers, employed at the appropriate levels, does not result insystemic toxicity.

SUMMARY OF THE INVENTION

It is thus a primary object of the invention to address theabove-described need in the art by providing a method for transdermallyadministering a nonsteroidal anti-inflammatory drug.

It is another object of the invention to provide such a method wherein ahydroxide-releasing agent is employed as a permeation enhancer toincrease the flux of the NSAID through a patient's skin or mucosaltissue.

It is still another object of the invention to provide such a methodwherein the amount of hydroxide-releasing agent employed is optimized toenhance permeation while minimizing or eliminating the possibility ofskin damage, irritation or sensitization.

It is an additional object of the invention to provide formulations anddrug delivery systems for carrying out the aforementioned methods.

Additional objects, advantages and novel features of the invention willbe set forth in part in the description that follows, and in part willbecome apparent to those skilled in the art upon examination of thefollowing, or may be learned by practice of the invention.

In one aspect of the invention, then, a method is provided forincreasing the rate at which a nonsteroidal anti-inflammatory drugpermeates through the body surface of a patient. The method involvesadministering the nonsteroidal anti-inflammatory drug to a predeterminedarea of the patient's body surface in combination with ahydroxide-releasing agent in a predetermined amount effective to enhancethe flux of the drug through the body surface without causing damagethereto. The predetermined amount of the hydroxide-releasing enhancer ispreferably an amount effective to provide a pH at the body surface inthe range of about 8.0 to 13, preferably about 8.0 to 11.5, morepreferably about 8.5 to 11.5, during drug administration. If a skinpatch is used, this is the preferred pH at the interface between thebasal surface of the patch (i.e., the skin-contacting ormucosa-contacting surface of the patch) and the body surface. Theoptimal amount (or concentration) of any one hydroxide-releasing agentwill, however, depend on the specific hydroxide-releasing agent, i.e.,on the strength or weakness of the base, its molecular weight, and otherfactors as will be appreciated by those of ordinary skill in the art oftransdermal drug delivery. This optimal amount may be determined usingroutine experimentation to ensure that the pH at the body surface iswithin the aforementioned ranges, i.e., in the range of about 8.0 to 13,preferably about 8.0 to 11.5, more preferably about 8.5 to 11.5. Aconventional transdermal drug delivery device or “patch” may be used toadminister the active agent, in which case the drug andhydroxide-releasing agent are generally present in a drug reservoir orreservoirs. However, the drug and hydroxide-releasing agent may also beadministered to the body surface using a liquid or semisolidformulation. Alternatively, or in addition, the body surface may bepretreated with the enhancer, e.g., treated with a dilute solution ofthe hydroxide-releasing agent prior to transdermal drug administration.Such a solution will generally be comprised of a protic solvent (e.g.,water or alcohol) and have a pH in the range of about 8.0 to 13,preferably about 8.0 to 11.5, more preferably about 8.5 to 11.5.

In a related aspect of the invention, a composition of matter isprovided for delivering a nonsteroidal anti-inflammatory drug through abody surface using a hydroxide-releasing agent as a permeation enhancer.Generally, the formulation comprises (a) a therapeutically effectiveamount of a drug, (b) a hydroxide-releasing agent in an amount effectiveto enhance the flux of the drug through the body surface without causingdamage thereto, and (c) a pharmaceutically acceptable carrier suitablefor topical or transdermal drug administration. The composition may bein any form suitable for application to the body surface, and maycomprise, for example, a cream, lotion, solution, gel, ointment, pasteor the like, and/or may be prepared so as to contain liposomes,micelles, and/or microspheres. The composition may be directly appliedto the body surface or may involve use of a drug delivery device. Ineither case, it is preferred although not essential that water bepresent in order for the hydroxide-releasing agent to generate hydroxideions and thus enhance the flux of the active agent through the patient'sbody surface. Thus, a formulation or drug reservoir may be aqueous,i.e., contain water, or may be nonaqueous and used in combination withan occlusive overlayer so that moisture evaporating from the bodysurface is maintained within the formulation or transdermal systemduring drug administration. In some cases, however, e.g., with anocclusive gel, a nonaqueous formulation may be used with or without anocclusive overlayer.

In another aspect of the invention, a drug delivery system is providedfor the topical or transdermal administration of a nonsteroidalanti-inflammatory drug using a hydroxide-releasing agent as a permeationenhancer. The system will generally comprise: at least one drugreservoir containing the drug and the hydroxide-releasing agent in anamount effective to enhance the flux of the drug through the bodysurface without causing damage thereto; a means for maintaining thesystem in drug and enhancer transmitting relationship to the bodysurface; and a backing layer that serves as the outer surface of thedevice during use. The backing layer may be occlusive or nonocclusive,although it is preferably occlusive. The drug reservoir may be comprisedof a polymeric adhesive, which may serve as the basal surface of thesystem during use and thus function as the means for maintaining thesystem in drug and enhancer transmitting relationship to the bodysurface. The drug reservoir may also be comprised of a hydrogel, or itmay be a sealed pouch within a “patch”-type structure wherein the drugand hydroxide-releasing agent are present in the pouch as a liquid orsemi-solid formulation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the cumulative amount of ketoprofen froma matrix patch as described in Example 1.

FIG. 2 is a graph illustrating the cumulative amount of ibuprofen from agel described in Example 3.

FIG. 3 is a graph illustrating the cumulative amount of diclofenac froma matrix patch as described in Example 4.

FIG. 4 is a graph illustrating the cumulative amount of diclofenac froma gel described in Example 5.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and Overview

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to specific drug deliverysystems, device structures, enhancers or carriers, as such may vary. Itis also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a nonsteroidal anti-inflammatory drug” includes a mixtureof two or more such drugs, reference to “a hydroxide-releasing agent”includes mixtures of two or more hydroxide-releasing agents, and thelike.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The terms “drug” or “pharmacologically active agent” or “active agent”as used herein refer to a compound or composition of matter which, whenadministered to an organism (human or animal) induces a desiredpharmacologic and/or physiologic effect by local and/or systemic action.The active agents herein are nonsteroidal anti-inflammatory agents andpharmacologically acceptable salts, esters, amides, derivatives orprodrugs thereof.

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, prevention of the occurrence of symptoms and/or theirunderlying cause, and improvement or remediation of damage. The presentmethod of “treating” a patient, as the term is used herein, thusencompasses both prevention of a disorder in a predisposed individualand treatment of the disorder in a clinically symptomatic individual.

The term “hydroxide-releasing agent” as used herein is intended to meanan agent that releases free hydroxide ions in an aqueous environment.The agent may contain hydroxide ions and thus release the ions directly(e.g., an alkali metal hydroxide), or the agent may be on that is actedupon chemically in an aqueous environment to generate hydroxide ions(e.g., a metal carbonate).

By “therapeutically effective” amount is meant a nontoxic but sufficientamount of an active agent to provide the desired therapeutic effect.

By “transdermal” drug delivery is meant administration of a drug to theskin surface of an individual so that the drug passes through the skintissue and into the individual's blood stream, thereby providing asystemic effect. The term “transdermal” is intended to include“transmucosal” drug administration, i.e., administration of a drug tothe mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of anindividual so that the drug passes through the mucosal tissue and intothe individual's blood stream.

The term “topical administration” is used in its conventional sense tomean delivery of a topical drug of a pharmacologically active agent tothe skin or mucosa, as in, for example, the treatment of various skindisorders. Topical drug administration, in contrast to transdermaladministration, provides a local rather than a systemic effect. Unlessotherwise stated or implied, the terms “topical drug administration” and“transdermal drug administration” are used interchangeably.

The term “body surface” is used to refer to skin or mucosal tissue.

By “predetermined area” of skin or mucosal tissue, which refers to thearea of skin or mucosal tissue through which a drug-enhancer formulationis delivered, is intended a defined area of intact unbroken living skinor mucosal tissue. That area will usually be in the range of about 5 cm²to about 200 cm², more usually in the range of about 5 cm² to about 100cm², preferably in the range of about 20 cm² to about 60 cm². However,it will be appreciated by those skilled in the art of drug delivery thatthe area of skin or mucosal tissue through which drug is administeredmay vary significantly, depending on patch configuration, dose, and thelike.

“Penetration enhancement” or “permeation enhancement” as used hereinrelates to an increase in the permeability of the skin or mucosal tissueto the selected pharmacologically active agent, i.e., so that the rateat which the agent permeates therethrough (i.e., the “flux” of the agentthrough the body surface) is increased relative to the rate that wouldbe obtained in the absence of permeation enhancement. The enhancedpermeation effected through the use of such enhancers can be observed bymeasuring the rate of diffusion of drug through animal or human skinusing, for example a Franz diffusion apparatus as known in the art andas employed in the Examples herein.

An “effective” amount of a permeation enhancer is meant a nontoxic,nondamaging but sufficient amount of the enhancer to provide the desiredincrease in skin permeability and, correspondingly, the desired depth ofpenetration, rate of administration, and amount of drug delivered.

“Carriers” or “vehicles” as used herein refer to carrier materialssuitable for transdermal drug administration. Carriers and vehiclesuseful herein include any such materials known in the art which arenontoxic and does not interact with other components of the compositionin a deleterious manner.

The term “aqueous” refers to a formulation or drug delivery system thatcontains water or that becomes water-containing following application tothe skin or mucosal tissue.

Accordingly, the invention pertains to a method, composition and drugdelivery system for increasing the rate at which a nonsteroidalanti-inflammatory drug permeates through the body surface of a patient,wherein the method involves administering the drug to a predeterminedarea of the patient's body surface in combination with ahydroxide-releasing agent in an amount effective to enhance the flux ofthe drug through the body surface without causing damage thereto.

The Hydroxide-Releasing Agent

The “hydroxide-releasing agent” is a chemical compound that releasesfree hydroxide ions in the presence of an aqueous fluid. The aqueousfluid may be natural moisture at the skin surface, or a patch orcomposition that is used may contain added water, and/or be used inconnection with an occlusive backing. Similarly, any liquid or semisolidformulation that is used is preferably aqueous or used in conjunctionwith an overlayer of an occlusive material.

Any hydroxide-releasing agent may be used provided that the compoundreleases free hydroxide ions in the presence of an aqueous fluid.Examples of suitable hydroxide-releasing agents include, but are notlimited to, inorganic hydroxides, inorganic oxides, and alkali metal oralkaline earth metal salts of weak acids. Inorganic hydroxides include,for example, ammonium hydroxide, alkali metal hydroxide and alkalineearth metal hydroxides, such as sodium hydroxide, calcium hydroxide,potassium hydroxide, magnesium hydroxide, and the like. Inorganic oxidesinclude, for example, magnesium oxide, calcium oxide, and the like.Metal salts of weak acids include, for example, sodium acetate, sodiumborate, sodium carbonate, sodium bicarbonate, sodium phosphate(tribasic), sodium phosphate (dibasic), sodium borate, sodiummetaborate, potassium carbonate, potassium bicarbonate, potassiumcitrate, potassium acetate, potassium phosphate (dibasic), potassiumphosphate (tribasic), ammonium phosphate (dibasic), and the like.Preferred hydroxide-releasing agents are metal hydroxides such as sodiumhydroxide and potassium hydroxide.

It is important that the amount of hydroxide-releasing agent in anypatch or formulation is optimized so as to increase the flux of thenonsteroidal anti-inflammatory drug through the body surface whileminimizing any possibility of skin damage. In general, this means thatthe pH at the body surface in contact with a formulation or drugdelivery system of the invention (i.e., the interface between the bodysurface and the formulation or delivery system) should be in the rangeof approximately 8.0 to 13, preferably about 8.0 to 11.5, morepreferably about 8.5 to 11.5. This will typically although notnecessarily mean that the pH of the formulation or the drug compositioncontained within a delivery system will be in the range of approximately8.0 to 13, preferably 8.0 to 11.5, more preferably 8.5 to 11.5.

For inorganic hydroxides, the amount of hydroxide-releasing agent willtypically represent about 0.5 wt % to 4.0 wt %, preferably about 0.5 wt% to 3.0 wt %, more preferably about 0.75 wt % to 2.0 wt % and optimallyabout 1.0 wt %, of a topically applied formulation or of a drugreservoir or a drug delivery system, or “patch.” The aforementionedamount applies to formulations and patches in which the drug is (1) anuncharged molecule, either an uncharged, nonionizable compound or abasic drug in nonionized, free base form, or (2) a basic addition saltof an acid drug, and where (3) there are no additional species in theformulation or patch that could react with or be neutralized by theinorganic hydroxide. For formulations and patches in which the activeagent is an acid addition salt of a basic drug or is a drug that reactswith the hydroxide-releasing agent, e.g., an acidic drug in nonionized,free acid form, and/or wherein there are additional species in theformulations or systems that can be neutralized by or react with thehydroxide-releasing agent (i.e., acidic inactive ingredients), theamount of inorganic hydroxide will be the total of (1) the amountnecessary to neutralize or react with the drug and/or otherbase-neutralizable species, plus (2) about 0.5 wt % to 4.0 wt %,preferably about 0.5 wt % to 3.0 wt %, more preferably about 0.75 wt %to 2.0 wt % and optimally about 1.0 wt %, of the formulation or drugreservoir. That is, for acid addition salts of basic drugs andnonionized acidic drugs, the inorganic hydroxide should be present in anamount just sufficient to neutralize the drug, plus an additional amount(i.e., about 0.5 wt % to 4.0 wt %, preferably about 0.5 wt % to 3.0 wt%, more preferably about 0.75 wt % to 2.0 wt % and optimally about 1.0wt %) to enhance the flux of the drug through the skin or mucosaltissue. (By “neutralization” of a free acid is meant conversion of thefree acid, via ionization, to a salt.) For patches, the aforementionedpercentages are given relative to the total dry weight of theformulation components and the adhesive, gel or liquid reservoir.

For other hydroxide-releasing agents such as inorganic oxides and metalsalts of weak acids, the amount of hydroxide-releasing agent in theformulation or drug delivery system may be substantially higher, as highas about 20 wt %, in some cases as high as about 25 wt % or higher, butwill generally be in the range of about 2 wt % to about 20 wt %.

Still greater amounts of hydroxide-releasing agent may be used bycontrolling the rate and/or quantity of release of thehydroxide-releasing agent preferably during the drug delivery perioditself.

However, for all hydroxide-releasing agents herein, the optimum amountof any particular agent will depend on the strength or weakness of thebase, the molecular weight of the base, and other factors such as thenumber of ionizable sites in the drug administered and any other acidicspecies in the formulation or patch. One skilled in the art may readilydetermine the optimum amount for any particular agent by ensuring that aformulation or drug delivery system should in all cases be effective toprovide a pH at the skin surface in the range of about 8.0 to 13,preferably in the range of about 8.0 to 11.5, more preferably in therange of about 8.5 to 11.5, during application to reach the desired pHat the body surface. This in turn ensures that the degree of enhancementis optimized while the possibility of damage to the body surface iseliminated or at least substantially minimized.

The Active Agent(s)

Suitable nonsteroidal anti inflammatory agents that may be used in theformulations of the present invention include, but are not limited to:propionic acid derivatives such as ketoprofen, flurbiprofen, ibuprofen,naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen,oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, fenbufen andtiaprofenic acid; acetylsalicylic acid; apazone; diclofenac;difenpiramide; diflunisal; etodolac; flufenamic acid; indomethacin;ketorolac; meclofenamate; mefenamic acid; nabumetone; phenylbutazone;piroxicam; salicylic acid; sulindac; tolmetin; and combinations of anyof the foregoing. Preferred NSAIDs are ibuprofen, diclofenac sodium,ketoprofen, ketorolac and piroxicam.

Pharmaceutically acceptable analogs of such NSAIDs are suitable as well,including salts, esters, amides, prodrugs or other derivatives.

The NSAID or NSAIDs may be co-administered with one or more additionalactive agents, e.g.: antihistaminic agents such as diphenhydramine andchlorpheniramine (particularly diphenhydramine hydrochloride andchlorpheniramine maleate); corticosteroids, including lower potencycorticosteroids such as hydrocortisone, hydrocortisone-21-monoesters(e.g., hydrocortisone-21-acetate, hydrocortisone-21-butyrate,hydrocortisone-21-propionate, hydrocortisone-21-valerate, etc.),hydrocortisone-17,21-diesters (e.g., hydrocortisone-17,21diacetate,hydrocortisone-17-acetate-21-butyrate, hydrocortisone-17,21-dibutyrate,etc.), alclometasone, dexamethasone, flumethasone, prednisolone, andmethylprednisolone, as well as higher potency corticosteroids such asclobetasol propionate, betamethasone benzoate, betamethasonediproprionate, diflorasone diacetate, fluocinonide, mometasone furoate,triamcinolone acetonide, and the like; local anesthetic agents such asphenol, benzocaine, lidocaine, prilocaine and dibucaine; topicalanalgesics such as glycol salicylate, methyl salicylate, 1-menthol,d,1-camphor and capsaicin; and antibiotics. Suitable antibiotic agentsinclude, but are not limited to, antibiotics of the lincomycin family(referring to a class of antibiotic agents originally recovered fromstreptomyces lincolnensis), antibiotics of the tetracycline family(referring to a class of antibiotic agents originally recovered fromstreptomyces aureofaciens), and sulfur-based antibiotics, i.e.,sulfonamides. Exemplary antibiotics of the lincomycin family includelincomycin itself(6,8-dideoxy-6-[[(1-methyl-4propyl-2-pyrrolidinyl)-carbonyl]amino]-1-thio-L-threo-α-D-galacto-octopyranoside),clindamycin, the 7-deoxy, 7-chloro derivative of lincomycin (i.e.,7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]amino]-1-thio-L-threo-α-D-galacto-octopyranoside),related compounds as described, for example, in U.S. Pat. Nos.3,475,407, 3,509,127, 3,544,551 and 3,513,155, and pharmacologicallyacceptable salts and esters thereof. Exemplary antibiotics of thetetracycline family include tetracycline itself(4-(dimethylamino)1,4,4α,5,5α,6,11,12α-octahydro-3,6,12,12α-pentahydroxy-6-methyl-1,11-dioxo-2naphthacenecarboxamide),chlortetracycline, oxytetracycline, tetracycline, demeclocycline,rolitetracycline, methacycline and doxycycline and theirpharmaceutically acceptable salts and esters, particularly acid additionsalts such as the hydrochloride salt. Exemplary sulfur-based antibioticsinclude, but are not limited to, the sulfonamides sulfacetamide,sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine,sulfanethazine, sulfamethizole, sulfamethoxazole, and pharmacologicallyacceptable salts and esters thereof, e.g., sulfacetamide sodium.

To administer any one of the active agents in salt form, suitablepharmaceutically acceptable salts can be prepared using standardprocedures known to those skilled in the art of synthetic organicchemistry and described, for example, by J. March, Advanced OrganicChemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York:Wiley-Interscience, 1992). Acid addition salts are prepared from anactive agent in the free base form (e.g., compounds having a neutral—NH₂ group) using conventional means, involving reaction with a suitableacid. Suitable acids for preparing acid addition salts include bothorganic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvicacid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like, as well asinorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like. An acid addition saltmay be reconverted to the free base by treatment with a suitable base.Preparation of basic salts of acid moieties which may be present (e.g.,carboxylic acid groups) are prepared in a similar manner using apharmaceutically acceptable base such as sodium hydroxide, potassiumhydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide,trimethylamine, or the like.

Preparation of esters involves functionalization of carboxyl groups thatmay be present, as will be appreciated by those skilled in the arts ofpharmaceutical chemistry and drug delivery. Esters can be reconverted tothe free acids, if desired, by using conventional hydrogenolysis orhydrolysis procedures. Amides and prodrugs may also be prepared usingtechniques known to those skilled in the art or described in thepertinent literature. For example, amides may be prepared from esters,using suitable amine reactants, or they may be prepared from ananhydride or an acid chloride by reaction with ammonia or a lower alkylamine. Prodrugs are typically prepared by covalent attachment of amoiety which results in a compound that is therapeutically inactiveuntil modified by an individual's metabolic system.

For those active agents that are chiral in nature and can thus be inenantiomerically pure form or in a racemic mixture, the drug may beincorporated into the present dosage units either as the racemate or inenantiomerically pure form.

Formulations

The method of delivery of the NSAID may vary, but necessarily involvesapplication of a formulation or drug delivery system containing the drugand a hydroxide-releasing agent to a predetermined area of the skin orother tissue for a period of time sufficient to provide the desiredlocal or systemic effect. The method may involve direct application ofthe composition as an ointment, gel, cream, or the like, or may involveuse of a drug delivery device. In either case, water must be present inorder for the hydroxide-releasing agent to generate hydroxide ions andthus enhance the flux of the active agent through the patient's bodysurface. Thus, a formulation or drug reservoir may be aqueous, i.e.,contain water, or may be nonaqueous and used in combination with anocclusive overlayer so that moisture evaporating from the body surfaceis maintained within the formulation or transdermal system during drugadministration. In some cases, however, e.g., with an occlusive gel, anonaqueous formulation may be used with or without an occlusiveoverlayer.

Suitable formulations include ointments, creams, gels, lotions, pastes,and the like. Ointments, as is well known in the art of pharmaceuticalformulation, are semisolid preparations that are typically based onpetrolatum or other petroleum derivatives. The specific ointment base tobe used, as will be appreciated by those skilled in the art, is one thatwill provide for optimum drug delivery, and, preferably, will providefor other desired characteristics as well, e.g., emolliency or the like.As with other carriers or vehicles, an ointment base should be inert,stable, nonirritating and nonsensitizing. As explained in Remington: TheScience and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack PublishingCo., 1995), at pages 1399-1404, ointment bases may be grouped in fourclasses: oleaginous bases; emulsifiable bases; emulsion bases; andwater-soluble bases. Oleaginous ointment bases include, for example,vegetable oils, fats obtained from animals, and semisolid hydrocarbonsobtained from petroleum. Emulsifiable ointment bases, also known asabsorbent ointment bases, contain little or no water and include, forexample, hydroxystearin sulfate, anhydrous lanolin and hydrophilicpetrolatum. Emulsion ointment bases are either water-in-oil (W/O)emulsions or oil-in-water (O/W) emulsions, and include, for example,cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.Preferred water-soluble ointment bases are prepared from polyethyleneglycols of varying molecular weight; again, see Remington: The Scienceand Practice of Pharmacy for further information.

Creams, as also well known in the art, are viscous liquids or semisolidemulsions, either oil-in-water or water-in-oil. Cream bases arewater-washable, and contain an oil phase, an emulsifier and an aqueousphase. The oil phase, also called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol. The aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant.

As will be appreciated by those working in the field of pharmaceuticalformulation, gels are semisolid, suspension-type systems. Single-phasegels contain organic macromolecules distributed substantially uniformlythroughout the carrier liquid, which is typically aqueous, but also,preferably, contain an alcohol and, optionally, an oil. Preferred“organic macromolecules,” i.e., gelling agents, are crosslinked acrylicacid polymers such as the “carbomer” family of polymers, e.g.,carboxypolyalkylenes that may be obtained commercially under theCarbopol® trademark. Also preferred are hydrophilic polymers such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers andpolyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methyl cellulose; gums such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixingor stirring, or combinations thereof.

Lotions, which are preferred for delivery of cosmetic agents, arepreparations to be applied to the skin surface without friction, and aretypically liquid or semiliquid preparations in which solid particles,including the active agent, are present in a water or alcohol base.Lotions are usually suspensions of solids, and preferably, for thepresent purpose, comprise a liquid oily emulsion of the oil-in-watertype. Lotions are preferred formulations herein for treating large bodyareas, because of the ease of applying a more fluid composition. It isgenerally necessary that the insoluble matter in a lotion be finelydivided. Lotions will typically contain suspending agents to producebetter dispersions as well as compounds useful for localizing andholding the active agent in contact with the skin, e.g.,methylcellulose, sodium carboxymethyl-cellulose, or the like.

Pastes are semisolid dosage forms in which the active agent is suspendedin a suitable base. Depending on the nature of the base, pastes aredivided between fatty pastes or those made from a single-phase aqueousgels. The base in a fatty paste is generally petrolatum or hydrophilicpetrolatum or the like. The pastes made from single-phase aqueous gelsgenerally incorporate carboxymethylcellulose or the like as a base.

Formulations may also be prepared with liposomes, micelles, andmicrospheres. Liposomes are microscopic vesicles having a lipid wallcomprising a lipid bilayer, and can be used as drug delivery systemsherein as well. Generally, liposome formulations are preferred forpoorly soluble or insoluble pharmaceutical agents. Liposomalpreparations for use in the instant invention include cationic(positively charged), anionic (negatively charged) and neutralpreparations. Cationic liposomes are readily available. For example,N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes areavailable under the tradename Lipofectin® (GIBCO BRL, Grand Island,N.Y.). Similarly, anionic and neutral liposomes are readily available aswell, e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can beeasily prepared using readily available materials. Such materialsinclude phosphatidyl choline, cholesterol, phosphatidyl ethanolamine,dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol(DOPG), dioleoylphoshatidyl ethanolamine (DOPE), among others. Thesematerials can also be mixed with DOTMA in appropriate ratios. Methodsfor making liposomes using these materials are well known in the art.

Micelles are known in the art as comprised of surfactant moleculesarranged so that their polar headgroups form an outer spherical shell,while the hydrophobic, hydrocarbon chains are oriented towards thecenter of the sphere, forming a core. Micelles form in an aqueoussolution containing surfactant at a high enough concentration so thatmicelles naturally result. Surfactants useful for forming micellesinclude, but are not limited to, potassium laurate, sodium octanesulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodiumlauryl sulfate, docusate sodium, decyltrimethylammonium bromide,dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,tetradecyltrimethylammonium chloride, dodecylammonium chloride, polyoxyl8 dodecyl ether, polyoxyl 12 dodecyl ether, nonoxynol 10 and nonoxynol30. Micelle formulations can be used in conjunction with the presentinvention either by incorporation into the reservoir of a topical ortransdermal delivery system, or into a formulation to be applied to thebody surface.

Microspheres, similarly, may be incorporated into the presentformulations and drug delivery systems. Like liposomes and micelles,microspheres essentially encapsulate a drug or drug-containingformulation. They are generally although not necessarily formed fromlipids, preferably charged lipids such as phospholipids. Preparation oflipidic microspheres is well known in the art and described in thepertinent texts and literature.

Various additives, known to those skilled in the art, may be included inthe topical formulations. For example, solvents, including relativelysmall amounts of alcohol, may be used to solubilize certain drugsubstances. Other optional additives include opacifiers, antioxidants,fragrance, colorant, gelling agents, thickening agents, stabilizers,surfactants and the like. Other agents may also be added, such asantimicrobial agents, to prevent spoilage upon storage, i.e., to inhibitgrowth of microbes such as yeasts and molds. Suitable antimicrobialagents are typically selected from the group consisting of the methyland propyl esters of p-hydroxybenzoic acid (i.e., methyl and propylparaben), sodium benzoate, sorbic acid, imidurea, and combinationsthereof.

For those drugs having an unusually low rate of permeation through theskin or mucosal tissue, it may be desirable to include a secondpermeation enhancer in the formulation in addition to thehydroxide-releasing agent, although in a preferred embodiment thehydroxide-releasing agent is administered without any other permeationenhancers. Any other enhancers should, like the hydroxide-releasingagent itself, minimize the possibility of skin damage, irritation, andsystemic toxicity. Examples of suitable secondary enhancers (or“co-enhancers”) include, but are not limited to: ethers such asdiethylene glycol monoethyl ether (available commercially asTranscutol®) and diethylene glycol monomethyl ether; surfactants such assodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide,benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80)and lecithin (U.S. Pat. No. 4,783,450); alcohols such as ethanol,propanol, octanol, benzyl alcohol, and the like; fatty acids such aslauric acid, oleic acid and valeric acid; fatty acid esters such asisopropyl myristate, isopropyl palmitate, methylpropionate, and ethyloleate; polyols and esters thereof such as polyethylene glycol, andpolyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No.4,568,343); amides and other nitrogenous compounds such as urea,dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone,1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; and organic acids, particularlycitric acid and succinic acid. Azone® and sulfoxides such as DMSO andC₁₀MSO may also be used, but are less preferred. As noted earlierherein, Percutaneous Penetration Enhancers, eds. Smith et al. (CRCPress, 1995) provides an excellent overview of the field and furtherinformation concerning possible secondary enhancers for use inconjunction with the present invention.

The formulation may also contain irritation-mitigating additives tominimize or eliminate the possibility of skin irritation or skin damageresulting from the drug, the enhancer, or other components of theformulation. Suitable irritation-mitigating additives include, forexample: α-tocopherol; monoamine oxidase inhibitors, particularly phenylalcohols such as 2-phenyl-1-ethanol; glycerin; salicylic acids andsalicylates; ascorbic acids and ascorbates; ionophores such as monensin;amphiphilic amines; ammonium chloride; N-acetylcysteine; cis-urocanicacid; capsaicin; and chloroquine. The irritant-mitigating additive, ifpresent, may be incorporated into the present formulations at aconcentration effective to mitigate irritation or skin damage, typicallyrepresenting not more than about 20 wt %, more typically not more thanabout 5 wt %, of the formulations.

The concentration of the active agent in the formulation can vary agreat deal, and will depend on a variety of factors, including thedisease or condition to be treated, the nature and activity of theactive agent, the desired effect, possible adverse reactions, theability and speed of the active agent to reach its intended target, andother factors within the particular knowledge of the patient andphysician. The formulations will typically contain on the order of about0.5 wt % to 50 wt % active agent, preferably about 0.5 wt % to 5 wt %active agent, optimally about 5 wt % to 20 wt % active agent.

Drug Delivery Systems

An alternative and preferred method involves the use of a drug deliverysystem, e.g., a topical or transdermal “patch,” wherein the active agentis contained within a laminated structure that is to be affixed to theskin. In such a structure, the drug composition is contained in a layer,or “reservoir,” underlying an upper backing layer. The laminatedstructure may contain a single reservoir, or it may contain multiplereservoirs.

In one embodiment, the reservoir comprises a polymeric matrix of apharmaceutically acceptable adhesive material that serves to affix thesystem to the skin during drug delivery; typically, the adhesivematerial is a pressure-sensitive adhesive (PSA) that is suitable forlong-term skin contact, and which should be physically and chemicallycompatible with the active agent, hydroxide-releasing agent, and anycarriers, vehicles or other additives that are present. Examples ofsuitable adhesive materials include, but are not limited to, thefollowing: polyethylenes; polysiloxanes; polyisobutylenes;polyacrylates; polyacrylamides; polyurethanes; plasticizedethylene-vinyl acetate copolymers; and tacky rubbers such aspolyisobutene, polybutadiene, polystyrene-isoprene copolymers,polystyrene-butadiene copolymers, and neoprene(polychloroprene).Preferred adhesives are polyisobutylenes.

The backing layer functions as the primary structural element of thetransdermal system and provides the device with flexibility and,preferably, occlusivity. The material used for the backing layer shouldbe inert and incapable of absorbing drug, hydroxide-releasing agent orcomponents of the formulation contained within the device. The backingis preferably comprised of a flexible elastomeric material that servesas a protective covering to prevent loss of drug and/or vehicle viatransmission through the upper surface of the patch, and will preferablyimpart a degree of occlusivity to the system, such that the area of thebody surface covered by the patch becomes hydrated during use. Thematerial used for the backing layer should permit the device to followthe contours of the skin and be worn comfortably on areas of skin suchas at joints or other points of flexure, that are normally subjected tomechanical strain with little or no likelihood of the device disengagingfrom the skin due to differences in the flexibility or resiliency of theskin and the device. The materials used as the backing layer are eitherocclusive or permeable, as noted above, although occlusive backings arepreferred, and are generally derived from synthetic polymers (e.g.,polyester, polyethylene, polypropylene, polyurethane, polyvinylidinechloride, and polyether amide), natural polymers (e.g., cellulosicmaterials), or macroporous woven and nonwoven materials.

During storage and prior to use, the laminated structure includes arelease liner. Immediately prior to use, this layer is removed from thedevice so that the system may be affixed to the skin. The release linershould be made from a drug/vehicle impermeable material, and is adisposable element which serves only to protect the device prior toapplication. Typically, the release liner is formed from a materialimpermeable to the pharmacologically active agent and thehydroxide-releasing agent, and which is easily stripped from thetransdermal patch prior to use.

In an alternative embodiment, the drug-containing reservoir and skincontact adhesive are present as separate and distinct layers, with theadhesive underlying the reservoir. In such a case, the reservoir may bea polymeric matrix as described above. Alternatively, the reservoir maybe comprised of a liquid or semisolid formulation contained in a closedcompartment or “pouch,” or it may be a hydrogel reservoir, or may takesome other form. Hydrogel reservoirs are particularly preferred herein.As will be appreciated by those skilled in the art, hydrogels aremacromolecular networks that absorb water and thus swell but do notdissolve in water. That is, hydrogels contain hydrophilic functionalgroups that provide for water absorption, but the hydrogels arecomprised of crosslinked polymers that give rise to aqueousinsolubility. Generally, then, hydrogels are comprised of crosslinkedhydrophilic polymers such as a polyurethane, a polyvinyl alcohol, apolyacrylic acid, a polyoxyethylene, a polyvinylpyrrolidone, apoly(hydroxyethyl methacrylate) (poly(HEMA)), or a copolymer or mixturethereof. Particularly preferred hydrophilic polymers are copolymers ofHEMA and polyvinylpyrrolidone.

Additional layers, e.g., intermediate fabric layers and/orrate-controlling membranes, may also be present in any of these drugdelivery systems. Fabric layers may be used to facilitate fabrication ofthe device, while a rate-controlling membrane may be used to control therate at which a component permeates out of the device. The component maybe a drug, a hydroxide-releasing agent, an additional enhancer, or someother component contained in the drug delivery system.

A rate-controlling membrane, if present, will be included in the systemon the skin side of one or more of the drug reservoirs. The materialsused to form such a membrane are selected to limit the flux of one ormore components contained in the drug formulation. Representativematerials useful for forming rate-controlling membranes includepolyolefins such as polyethylene and polypropylene, polyamides,polyesters, ethylene-ethacrylate copolymer, ethylene-vinyl acetatecopolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinylethylacetate copolymer, ethylene-vinyl propylacetate copolymer,polyisoprene, polyacrylonitrile, ethylene-propylene copolymer, and thelike.

Generally, the underlying surface of the transdermal device, i.e., theskin contact area, has an area in the range of about 5 cm² to 200 cm²,preferably 5 cm² to 100 cm², more preferably 20 cm² to 60 cm². That areawill vary, of course, with the amount of drug to be delivered and theflux of the drug through the body surface. Larger patches will benecessary to accommodate larger quantities of drug, while smallerpatches can be used for smaller quantities of drug and/or drugs thatexhibit a relatively high permeation rate.

Such drug delivery systems may be fabricated using conventional coatingand laminating techniques known in the art. For example, adhesive matrixsystems can be prepared by casting a fluid admixture of adhesive, drugand vehicle onto the backing layer, followed by lamination of therelease liner. Similarly, the adhesive mixture may be cast onto therelease liner, followed by lamination of the backing layer.Alternatively, the drug reservoir may be prepared in the absence of drugor excipient, and then loaded by “soaking” in a drug/vehicle mixture. Ingeneral, transdermal systems of the invention are fabricated by solventevaporation, film casting, melt extrusion, thin film lamination, diecutting, or the like. The hydroxide-releasing agent will generally beincorporated into the device during patch manufacture rather thansubsequent to preparation of the device.

In a preferred delivery system, an adhesive overlayer that also servesas a backing for the delivery system is used to better secure the patchto the body surface. This overlayer is sized such that it extends beyondthe drug reservoir so that adhesive on the overlayer comes into contactwith the body surface. The overlayer is useful because the adhesive/drugreservoir layer may lose its adhesion a few hours after application dueto hydration. By incorporating such an adhesive overlayer, the deliverysystem remains in place for the required period of time.

Other types and configurations of transdermal drug delivery systems mayalso be used in conjunction with the method of the present invention,i.e., the use of a hydroxide-releasing agent as a permeation enhancer,as will be appreciated by those skilled in the art of transdermal drugdelivery. See, for example, Ghosh, Transdermal and Topical Drug DeliverySystems (Interpharm Press, 1997), particularly Chapters 2 and 8.

As with the topically applied formulations of the invention, thecomposition containing drug and hydroxide-releasing agent within thedrug reservoir(s) of these laminated system may contain a number ofcomponents. In some cases, the drug and hydroxide-releasing agent may bedelivered “neat,” i.e., in the absence of additional liquid. In mostcases, however, the drug will be dissolved, dispersed or suspended in asuitable pharmaceutically acceptable vehicle, typically a solvent orgel. Other components which may be present include preservatives,stabilizers, surfactants, and the like.

Utility

The amount of drug present in the formulations and drug delivery systemsof the invention and required to achieve an effective therapeutic resultdepends on many factors, such as the particular NSAID selected, theminimum necessary dosage of the drug for the particular indication beingtreated, the solubility and permeability of the carrier and adhesivelayer, and the period of time for which the device will be affixed tothe skin or other body surface. The minimum amount of drug is determinedby the requirement that sufficient quantities of drug must be present inthe device to maintain the desired rate of release over the given periodof application. The maximum amount for safety purposes is determined bythe requirement that the quantity of drug present cannot exceed a rateof release that reaches toxic levels. Generally, the maximumconcentration is determined by the amount of agent that can be receivedin the carrier without producing adverse histological effects such asirritation, an unacceptably high initial pulse of agent into the body,or adverse effects on the characteristics of the delivery device such asthe loss of tackiness, viscosity, or deterioration of other properties.

The transdermal delivery formulations and systems of the invention areused to treat an individual with an NSAID-responsive condition ordisorder. Typically, the formulations are employed as anti-inflammatoryand/or analgesic compositions, and may be used to treat individualssuffering from rheumatic or arthritic disorders, including, for example:rheumatoid arthritis (RA), degenerative joint disease (also known as DJDand “osteoarthritis”); juvenile rheumatoid arthritis (JRA); psoriaticarthritis; gouty arthritis; ankylosing spondylitis; and lupuserythematoses such as systemic lupus erythematosus and discoid lupuserythematosus.

Other potential uses for the formulation of the present inventioninclude, but are not limited to, treating fever (via the anti-pyreticproperty of NSAIDs) or myocardial infarction (MI), transient ischemicattacks, and acute superficial thrombophlebitis (via inhibition ofplatelet aggregation). Further non-limiting uses for NSAIDs includeeither single or adjuvant therapy for ankylosing spondylitis, bursitis,cancer-related pain, dysmenorrhea, gout, headaches, muscular pain,tendonitis, and pain associated with medical procedures such as dental,gynecological, oral, orthopedic, post-partum and urological procedures.

As noted above, the amount of active compound administered will dependon a number of factors and will vary from subject to subject and dependon the particular active agent administered, the particular disorder orcondition, the severity of the symptoms, the subject's age, weight andgeneral condition, and the judgment of the prescribing physician. Otherfactors specific to transdermal drug delivery include the solubility andpermeability of the carrier and the adhesive layer in a drug deliverysystem, if one is used, and the period of time for which such a devicewill be affixed to the skin or other body surface. Generally, however,and by way of example, a daily dosage of ketorolac using the presentformulations and systems will be in the range of approximately 10 mg to40 mg, a daily dosage of piroxicam using the present formulations andsystems will be in the range of approximately 10 mg to 40 mg, and adaily dosage of ibuprofen using the present formulations and systemswill be in the range of approximately 200 mg/day to 1600 mg/day.

The invention accordingly provides a novel and highly effective meansfor increasing the flux of a nonsteroidal anti-inflammatory drug throughthe body surface (skin or mucosal tissue) of a human or animal. Thehydroxide-releasing agents discussed herein, employed in specificamounts relative to a formulation or drug reservoir, may be used aspermeation enhancers with a variety of nonsteroidal anti-inflammatorydrugs, including, but not limited to, ibuprofen, diclofenac sodium,ketoprofen, ketorolac and piroxicam. Surprisingly, the increase inpermeation is not accompanied by any noticeable tissue damage,irritation, or sensitization. The invention thus represents an importantadvance in the field of drug delivery.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, theforegoing description, as well as the examples which follow, areintended to illustrate and not limit the scope of the invention. Otheraspects, advantages and modifications will be apparent to those skilledin the art to which the invention pertains. All patents, patentapplications, journal articles and other references cited herein areincorporated by reference in their entireties.

EXAMPLE 1

An in vitro skin permeation study was conducted using four ketoprofentransdermal systems. The formulations used to prepare these systems arelisted in Table 1, which includes weight and weight percent of eachcomponent of the formulations. The weight of sodium hydroxide was 0 g,0.19 g, 0.215 g, and 0.225 g for formulation #Keto-P3H16, -P3H17,-P3H18, and -P3H19, respectively. Each formulation was coated on arelease liner and dried in an oven at 55° C. for two hours to removewater and other solvents. The dried drug-in-adhesive/release liner filmwas laminated to a backing film. The backing/drug-in-adhesive/releaseliner laminate was then cut into discs with a diameter of 11/16 inch.The theoretical percent weight for each ingredient after drying(calculated assuming all volatile ingredients were completely removedduring drying) is set forth in Table 2.

The in vitro permeation of ketoprofen through human cadaver skin fromthese discs was performed using Franz diffusion cells with a diffusionarea of 1 cm². Human cadaver skin was cut to a proper size and placed ona flat surface with the stratum corneum side facing up. The releaseliner was peeled away from the disc laminate. Thebacking/drug-in-adhesive film was placed and pressed on the skin withthe adhesive side facing the stratum corneum. The skin/adhesive/backinglaminate was clamped between the donor and receiver chambers of thediffusion cell with the skin side facing the receiver solution. Fivediffusion cells were used for each formulation.

Normal saline was used as the receiver solution. The volume of receiversolution was 8 ml. The entire receiver solution was collected andreplaced with fresh saline at each time point. The receiver solutioncollected was analyzed by HPLC to determine the concentration ofketoprofen. The cumulative amount of ketoprofen that permeated acrossthe human cadaver skin was calculated using the measured ketoprofenconcentrations in the receiver solutions, which were plotted versus timeand shown in FIG. 1.

Since ketoprofen is a free acid, it reacts with NaOH. The concentrationof NaOH in the system after the reaction is completed depends on theamount of ketoprofen added. The remaining NaOH concentration after thereaction is completed is defined as “excess NaOH concentration,” whichis calculated by the following equation.[NaOH_(excess)]=[NaOH_(total)]−[NaOH_(needed for neutralization)]The excess NaOH concentrations for three ketoprofen systems,#Keto-P3H16, -P3H17, -P3H18, and -P3H19, were calculated and are setforth in Table 3.

The pH of each patch was measured using the following procedures. A 2.5cm² circular patch was punched out. Ten ml purified water was pipettedinto a glass vial, and a stir bar was added; the liner was removed fromthe patch and placed in the vial along with the patch. The vial was thenplaced on a stir plate and the water/patch/liner mixture was stirred for5 minutes, at which point the liner was removed from the vial anddiscarded. The vial was again placed on a stir plate and stirringcontinued for an additional 18 hours. The stir bar was removed from thevial and the pH of the solution determined using a calibrated pH meter.The results are set forth in Table 3.

TABLE 1 Weight and Weight Percent of Each Component (Based on TotalSolution Weight) for Four Ketoprofen Transdermal Systems Keto-P3H16Keto-P3H17 Keto-P3H18 Keto-P3H19 Ketoprofen 1.2 g  1.2 g  1.2 g  1.2 g(16.7%) (15.8%) (15.7%) (15.7%) NaOH 0 0.19 g 0.215 g 0.225 g  (2.5%) (2.8%)  (2.9%) DI water 0 0.19 g 0.215 g 0.225 g  (2.5%)  (2.8%) (2.9%) PIB adhesive   4 g   4 g    4 g    4 g (30% solid) (55.6%)(52.8%) (52.4%) (52.3%) Methylal   2 g   2 g    2 g    2 g (27.8%)(26.4%) (26.2%) (26.1%)

TABLE 2 Weight and Theoretical Weight Percent of Each Component in theDried Film for Four Ketoprofen Transdermal Systems Keto-P3H16 Keto-P3H17Keto-P3H18 Keto-P3H19 Ketoprofen 1.2 g  1.2 g  1.2 g  1.2 g (50%)(45.9%) (45.9%) (45.7%) NaOH 0 0.19 g 0.215 g 0.225 g  (7.3%)  (8.2%) (8.6%) PIB adhesive 1.2 g  1.2 g  1.2 g  1.2 g (50%) (46.3%) (45.9%)(45.7%)

TABLE 3 Excess NaOH Concentration and pH of Four Ketoprofen TransdermalSystems Keto-P3H16 Keto-P3H17 Keto-P3H18 Keto-P3H19 Excess NaOH 0.05%1.00% 1.38% Concentration pH 3.68 8.60 10.10 10.57

Even though patch #Keto-P3H17 contained 7.3% NaOH (Table 2), thecumulative amount of ketoprofen that permeated across the human cadaverskin at 24 hours (61.7 μg/cm², FIG. 1) was only slightly higher thanthat from the formulation without NaOH (Keto-P3H16, 35.2 μg/cm²). Thismay be due to the consumption of NaOH by the reaction between NaOH andketoprofen, which reduced the NaOH concentration to only 0.05% as theexcess NaOH concentration (Table 3). This result indicated that thepermeation of ketoprofen could be enhanced with an excess NaOHconcentration as low as 0.05%.

The cumulative amount of ketoprofen that permeated across human cadaverskin at 24 hours increased from 61.7 μg/cm² to 402.7 μg/cm² when thecalculated excess NaOH concentration in the dried patch was increasedfrom 0.05% to 1.38%. The cumulative amount of ketoprofen that permeatedacross human cadaver skin at 24 hours from the formulation with anexcess NaOH concentration of 1.00% (Keto-P3H18, 315.8 μg/cm²) is about 5times higher than that from the formulation with an excess NaOHconcentration of 0.05% (Keto-P3H17, 61.7 μg/cm²).

The pH of the ketoprofen patch increased from 8.60 to 10.57 when thecalculated excess NaOH concentration in the dried patch was increasedfrom 0.05% to 1.38%.

EXAMPLE 2

A human skin irritation study was performed using seven transdermalsystems, which are listed below.

-   -   Patch #Keto-IT1 (containing no ketoprofen, no NaOH)    -   Patch #Keto-IT2 (containing ketoprofen, no NaOH)    -   Patch #Keto-IT7    -   Patch #Keto-IT8    -   Patch #Keto-IT9    -   Patch #Keto-IT10    -   Patch containing petrolatum

The patch containing petrolatum was used as a control, which was anocclusive chamber (Hilltop, Cincinnati, Ohio) containing petrolatum heldin place with paper tape. The following procedures were used to preparethe systems with the exception of the system containing petrolatum. Theformulations used to prepare these systems are listed in Table 4, whichinclude weight and weight percent of each component in the formulations.The weight of sodium hydroxide was 0.6 g, 0.65 g, 0.69 g, and 0.73 g forformulation #Keto-IT7, -IT8, -IT9 and -IT10 respectively. Eachformulation was coated onto a release liner and dried in an oven at 55°C. for two hours to remove water and other solvents. The drieddrug-in-adhesive/release liner film was laminated to a backing film. Thebacking/drug-in-adhesive/release liner laminate was cut into round discswith a diameter of ½ inch. The theoretical percent weight for eachingredient after drying is listed in Table 5, which was calculatedassuming all the volatile ingredients were completely removed duringdrying.

Ten healthy human subjects were included in the skin irritation study.Each subject worn seven patches listed above on the arms for 24 hours.An adhesive film with a diameter of ⅞ inch was applied over each systemon the skin except the petrolatum patch to secure the system and to makethe system occlusive for 24 hours. After 24 hours, the patches wereremoved and the skin was scored on a 0-4 scale. The scoring scaleemployed is listed below. The skin was scored again at 48 hours.

-   -   0=negative    -   +=equivocal reaction (0.5)    -   1=erythema    -   2=erythema and induration    -   3=erythema, induration and vesicles    -   4=bullae

A skin permeation study was performed from formulation #Keto-IT7, -IT8,-IT9 and -IT10. Franz diffusion cells with a diffusion area of 1 cm²were used in this study. Human cadaver skin was cut to a proper size andplaced on a flat surface with the stratum corneum side facing up. Therelease liner was peeled away from the round disc laminate. Thebacking/drug-in-adhesive film was placed and pressed on the skin withthe adhesive side facing the stratum corneum. The skin/adhesive/backinglaminate was clamped between the donor and receiver chambers of thediffusion cell with the skin side facing the receiver solution. Threediffusion cells were used for each formulation.

Normal saline was used as the receiver solution. The volume of receiversolution was 8 ml. The receiver solution was collected at 24 hours andanalyzed by an HPLC for the concentration of ketoprofen. The amount ofketoprofen that permeated across the human cadaver skin was calculatedusing the measured ketoprofen concentrations in the receiver solutions,which are listed in Table 6.

The excess NaOH concentrations for four ketoprofen systems, #Keto -IT7,-IT8, -IT9 and -IT10 were calculated as the preceding examples andlisted in Table 6.

The pH of the patch was determined using the procedure of Example 1, andthe measured pH for each ketoprofen transdermal systems is also listedin Table 6.

TABLE 4 Weight and Weight Percent of Each Component (Based on TotalSolution Weight) for Four Ketoprofen Transdermal Systems Keto-IT7Keto-IT8 Keto-IT9 Keto-IT10 Ketoprofen 2.4 g 2.4 g 2.4 g 2.4 g (14.0%)(14.0%) (13.9%) (13.8%) NaOH 0.6 g 0.65 g  0.69 g  0.73 g   (3.5%) (3.8%)  (4.0%)  (4.2%) DI water 0.6 g 0.65 g  0.69 g  0.73 g   (3.5%) (3.8%)  (4.0%)  (4.2%) PIB adhesive (30% solid)   8 g   8 g   8 g   8 g(46.8%) (46.5%) (46.3%) (46.1%) Tetraglycol 0.5 g 0.5 g 0.5 g 0.5 g (2.9%)  (2.9%)  (2.9%)  (2.9%) Isopropylmyristate 0.4 g 0.4 g 0.4 g 0.4g  (2.3%)  (2.3%)  (2.3%)  (2.3%) Methyl salicylate 0.6 g 0.6 g 0.6 g0.6 g  (3.5%)  (3.5%)  (3.5%)  (3.5%) Methylal   4 g   4 g   4 g   4 g(23.4%) (23.3%) (23.3%) (23.0%)

TABLE 5 Weight and Theoretical Weight Percent of Each Component in theDried Film for Four Ketoprofen Transdermal Systems Keto-IT7 Keto-IT8Keto-IT9 Keto-IT10 Ketoprofen 2.4 g 2.4 g 2.4 g 2.4 g (34.8%) (34.5%)(34.3%) (34.1%) NaOH 0.6 g 0.65 g  0.69 g  0.73 g   (8.7%)  (9.4%) (9.9%) (10.4%) PIB adhesive 2.4 g 2.4 g 2.4 g 2.4 g (34.0%) (34.5%)(34.3%) (34.1%) Tetraglycol 0.5 g 0.5 g 0.5 g 0.5 g  (7.2%)  (7.2%) (7.2%)  (7.1%) Isopropylmyristate 0.4 g 0.4 g 0.4 g 0.4 g  (5.8%) (5.8%)  (5.7%)  (5.7%) Methyl salicylate 0.6 g 0.6 g 0.6 g 0.6 g (8.7%)  (8.6%)  (8.6%)  (8.5%)

TABLE 6 Excess NaOH Concentration, Cumulative Amount of Ketoprofenacross Skin at 24 Hours and pH of Four Ketoprofen Transdermal SystemsKeto- Keto- Keto- Keto- IT7 IT8 IT9 IT10 pH 10.06 10.81 11.04 11.18Excess NaOH Concentration 3.22% 3.92% 4.47% 5.01% Cumulative amountacross 0.17 0.34 0.54 1.52 skin at 24 hours mg/cm²

The cumulative amount of ketoprofen that permeated across the humancadaver skin at 24 hours increased from 0.17 mg/cm² to 1.52 mg/cm² whenthe calculated excess NaOH concentration in the dried patch wasincreased from 3.22% to 5.01%. The excess NaOH concentration and thecumulative amount of ketoprofen across skin at 24 hours and the patch pHfor Keto-IT8 was 0.34 mg/cm² and 10.81 respectively, which was about thesame as those for Keto-P3H18 shown in Example 1 (0.32 mg/cm², pH=10.10).However, the excess NaOH concentration for Keto-IT8 (3.92%) was higherthan that for Keto-P3H18 (1.00%) which may be due to the consumption ofNaOH through reactions between NaOH and components other than ketoprofenin the Keto-IT8 formulation.

The irritation scores obtained indicate that irritation from this patchwas insignificant.

EXAMPLE 3

An in vitro skin permeation study was conducted using four ibuprofentransdermal gels. The formulations used to prepare these gels are listedin Table 7, which includes weight and weight percent of each componentin the formulations. The weight of sodium hydroxide was 0 g, 0.115 g,0.135 g, and 0.15 g for formulation #Ibu-GH81, -GH82, -GH83, and -GH84respectively.

The in vitro permeation of ibuprofen through human cadaver skin fromthese gels was performed using Franz diffusion cells with a diffusionarea of 1 cm². Human cadaver skin was cut to a proper size and clampedbetween the donor and receiver chambers of the diffusion cell with thestratum corneum side facing the donor solution. Three diffusion cellswere used for each formulation.

Normal saline was used as the receiver solution. The volume of receiversolution was 8 ml. The entire receiver solution was collected andreplaced with fresh saline at each time point. The receiver solutioncollected was analyzed by an HPLC for the concentration of ibuprofen.The cumulative amount of ibuprofen across human cadaver skin wascalculated using the measured ibuprofen concentrations in the receiversolutions, which were plotted versus time and shown in FIG. 2.

The excess NaOH concentration for three ibuprofen gels, #Ibu-GH81,-GH82, GH83, and -GH84, were calculated and listed in Table 8.

The pH of each gel was determined as done previously. The measured pHsfor the ibuprofen gels are listed in Table 8.

TABLE 7 Weight and Weight Percent of Each Component (Based on TotalSolution Weight) for Four Ibuprofen Transdermal Gels Ibu-GH81 Ibu-GH82Ibu-GH83 Ibu-GH84 Ibuprofen 0.6 g 0.6 g   0.6 g  0.6 g (36.8%) (32.3%)(31.6%) (31.1%) NaOH 0 0.115 g  0.135 g  0.15 g  (6.2%)  (7.1%)  (7.8%)Ethanol 0.4 g  0.4 g  0.4 g  0.4 g (24.5%) (21.5%) (21.1%) (20.7%) DIWater 0.6 g 0.715 g  0.735 g  0.75 g (36.8%) (38.4%) (38.7%) (38.9%)HPMCP* 0.03 g  0.03 g 0.03 g 0.03 g  (1.8%)  (1.6%)  (1.6%)  (1.6%)*HPMCP = Hydroxypropyl methyl cellulose phthalate

TABLE 8 Excess NaOH Concentration and pH of Four Ibuprofen TransdermalGels Ibu-GH81 Ibu-GH82 Ibu-GH83 Ibu-GH84 Excess NaOH 0%   0.98% 1.74%Concentration pH 4.57 6.58 11.83 12.22

The cumulative amount of ibuprofen across human cadaver skin at 24 hoursincreased from 0.33 mg/cm² to 5.74 mg/cm² (FIG. 2) when the calculatedexcess NaOH concentration in the gel was increased from 0% to 1.74%. Thecumulative amount of ibuprofen that permeated across the human cadaverskin at 24 hours from the formulation with an excess NaOH concentrationof 0.98% (lbu-GH83, 1.12 mg/cm²) is about 3 times higher than that fromthe formulation with an excess NaOH concentration of 0% (Ibu-GH82, 0.33mg/cm²).

The pH of the ibuprofen patch determined using the procedures of theprevious examples increased from 6.58 to 12.22 when the calculatedexcess NaOH concentration in the gel was increased from 0% to 1.74%. Theskin irritation could be related to the pH of the gel, which depends onthe excess NaOH concentration.

EXAMPLE 4

An in vitro skin permeation study was conducted using four diclofenacsodium transdermal systems. The formulations used to prepare thesesystems are listed in Table 9, which include weight and weight percentof each ingredient in the formulations. The weight of sodium hydroxide(NaOH) was 0 g, 0.035 g, 0.05 g, and 0.1 g for formulation #Diclo-P1O,-P11, -P12, and -P13 respectively. Each formulation was coated on arelease liner and dried in an oven at 55 □C for two hours to removewater and other solvents. The dried drug-in-adhesive/release liner filmwas laminated to a backing film. The backing/drug-in-adhesive/releaseliner laminate was then cut into round discs with a diameter of 11/16inch. The theoretical percent weight for each ingredient after drying(calculated assuming all the volatile ingredients were completelyremoved during drying) is listed in Table 10.

The in vitro permeation of diclofenac sodium through human cadaver skinfrom these discs was performed using Franz-type diffusion cells with adiffusion area of 1 cm². The volume of receiver solution was 8 ml. Humancadaver skin was cut to desired size and placed on a flat surface withthe stratum corneum side facing up. The release liner was peeled awayfrom the disc laminate. The backing/drug-in-adhesive film was placed andpressed on the skin with the adhesive side facing the stratum corneum.The skin/adhesive/backing laminate was clamped between the donor andreceiver chambers of the diffusion cell with the skin side facing thereceiver solution. Three diffusion cells were used for each formulation.

The cells were filled with 10% ethanol/90% water solution. The receiversolution was completely withdrawn and replaced with fresh ethanol/watersolution at each time point. The samples taken were analyzed by an HPLCfor the concentration of diclofenac sodium in the receiver solution. Thecumulative amount of diclofenac sodium across human cadaver skin wascalculated using the measured diclofenac sodium concentrations in thereceiver solutions, which are shown in Table 11 and FIG. 3.

Since diclofenac sodium is not expected to react with NaOH, the NaOHconcentration listed in Table 10 equals the excess NaOH concentration.

The pH of the patch was determined using the following procedures. A 2.5cm² circular patch was punched out. Ten ml purified water was pipettedinto a glass vial, and a stir bar was added, the liner was removed frompatch and placed in the vial along with the patch. The vial was thenplaced on a stir plate and the water/patch/liner mixture was stirred for5 minutes, at which point the liner was removed from the vial anddiscard. The vial was again placed on a stir plate and stirringcontinued for an additional 18 hours. After 18 hours, the stir bar wasremoved from vial and the pH of the solution determined using acalibrated pH meter.

The measured pHs for the diclofenac sodium transdermal systems arelisted in Table 12.

TABLE 9 Weight and Weight Percent of Each Component (Based on TotalSolution Weight) for Four Diclofenac Sodium Transdermal SystemsDiclo-P10 Diclo-P11 Diclo-P12 Diclo-P13 Diclofenac sodium 0.6 g 0.6 g0.6 g 0.6 g  (9.2%)  (9.1%)  (9.0%)  (9.0%) Propylene glycol 0.9 g 0.9 g0.9 g 0.9 g (13.9%) (13.7%) (13.6%) (13.4%) NaOH 0 0.035 g  0.05 g  0.1g  (0.5%)  (0.8%)  (1.5%) PIB adhesive (30% solid)   4 g   4 g   4 g   4g (61.5%) (60.9%) (60.6%) (59.7%) Heptane   1 g   1 g   1 g   1 g(15.4%) (15.2%) (15.2%) (14.9%) DI water 0 0.035 g 0.05 g  0.1 g  (0.5%) (0.8%)  (1.5%)

TABLE 10 Weight and Theoretical Weight Percent of Component in the DriedFilm for Four Diclofenac Sodium Transdermal Systems Diclo-P10 Diclo-P11Diclo-P12 Diclo-P13 Diclofenac sodium 0.6 g 0.6 g 0.6 g 0.6 g (22.2%)(21.9%) (21.8%) (21.4%) Propylene glycol 0.9 g 0.9 g 0.9 g 0.9 g (33.3%)(32.9%) (32.7%) (32.1%) NaOH 0 0.035 g  0.05 g  0.1 g  (1.3%)  (1.8%) (3.6%) PIB adhesive (30% solid) 1.2 g 1.2 g 1.2 g 1.2 g (44.4%) (43.9%)(43.6%) (42.9%)

TABLE 11 Cumulative Amount of PPA-HCl across human cadaver skin forDiclofenac Sodium Transdermal Systems (μg/cm²) Diclo-P10 Diclo-P11Diclo-P12 Diclo-P13   5 hours  0.5  659.0 1437.8 2010.5 10.5 hours  4.71587.6 2619.3 2992.9   20 hours 18.8 2273.7 3263.0 3513.1   24 hours28.4 2439.6 3420.6 3647.3

TABLE 12 Excess NaOH Concentration and pH of Four Diclofenac SodiumTransdermal Systems Diclo-P10 Diclo-P11 Diclo-P12 Diclo-P13 Excess NaOH0   1.3 1.8 3.6 Concentration (wt %) pH 7.17 10.59 10.72 11.28

The cumulative amount of diclofenac sodium across human cadaver skin at24 hours increased from 28.4 μg/cm² to 3647.3 μg/cm² when the calculatedexcess NaOH concentration in the dried patch was increased from 0% to3.6%. The cumulative amount of diclofenac sodium across human cadaverskin at 24 hours from the system containing 0% NaOH (Diclo-P11) was2439.6 μg/cm², which was about 85 times higher than that from theformulation without NaOH (28.4 μg/cm², #Diclo-P10).

The pH of the diclofenac sodium patch measured using the procedureslisted above increased from 7.17 to 11.28 when the calculated excessNaOH concentration in the dried patch was increased from 0% to 3.6%.

EXAMPLE 5

An in-vitro skin permeation study was conducted using four diclofenacsodium transdermal gels. The formulations used to prepare these gels arelisted in Table 53, which include weight and weight percent of eachingredient in the formulations. The weight of sodium hydroxide (NaOH)was 0 g, 0.02 g, 0.03 g, and 0.05 g for formulation #Diclo-DG25, -DG27,-DG28, and -DG29 respectively.

The in-vitro permeation of diclofenac sodium through human cadaver skinfrom these gels was performed using Franz-type diffusion cells with adiffusion area of 1 cm². Human cadaver skin was cut to desired size andclamped between the donor and receiver chambers of the diffusion cellwith the stratum corneum side facing the donor solution. Three diffusioncells were used for each formulation.

10% ethanol/90% water solution was used as the receiver solution. Thevolume of receiver solution was 8 ml. The receiver solution wascollected and replaced with fresh ethanol/water solution at each timepoint. The receiver solution collected was analyzed by an HPLC for theconcentration of diclofenac sodium. The cumulative amount of diclofenacsodium across human cadaver skin was calculated using the measureddiclofenac sodium concentrations in the receiver solutions, which areshown in Table 14 and FIG. 4.

Since diclofenac sodium is not expected to react with NaOH, the NaOHconcentration listed in Table 13 equals the excess NaOH concentration.

TABLE 13 Weight and Weight Percent of Each Component (Based on TotalSolution Weight) for Four Diclofenac Sodium Transdermal Gels Diclo-DG25Diclo-DG27 Diclo-DG28 Diclo-DG29 Diclofenac 0.3 g  0.3 g  0.3 g  0.3 gsodium (14.1%) (13.8%) (13.7%) (13.50%)  Propylene 0.6 g  0.6 g  0.6 g 0.6 g glycol (28.2%) (27.6%) (27.4%) (26.9%) Ethyl alcohol   1 g   1 g  1 g   1 g (46.9%) (46.1%) (45.7%) (44.8%) DI water 0.2 g 0.22 g 0.23 g0.25 g  (9.4%) (10.1%) (10.5%) (11.2%) HPMC 0.03 g  0.03 g 00.3 g 0.03 g (1.4%)  (1.4%)  (1.4%)  (1.3%) NaOH 0 0.02 g 0.03 g 0.05 g  (0.9%) (1.4%)  (2.2%)

TABLE 14 Cumulative Amount of PPA-HCl across human cadaver skin forDiclofenac Sodium Transdermal Gels (μg/cm²) Diclo-DG25 Diclo-DG27Diclo-DG28 Diclo-DG29   5 hours 16.8  50.6 175.9  585.2 10.5 hours 29.8147.5 503.5 1499.8   20 hours 53.4 252.3 896.4 1988.1   24 hours 65.3270.4 1023.3  2036.8

TABLE 15 Excess NaOH Concentration of Four Diclofenac Sodium TransdermalGels Diclo- Diclo- Diclo- Diclo- DG25 DG27 DG28 DG29 Excess NaOH 0 0.91.4 2.2 Concentration (wt %)

The cumulative amount of diclofenac sodium across human cadaver skin at24 hours increased from 65.3 μg/cm² to 2036.8 μg/cm² when the calculatedexcess NaOH concentration in the gel was increased from 0% to 2.2%(Table 15). The cumulative amount of diclofenac sodium across humancadaver skin at 24 hours from the gel containing 0.9% NaOH (Diclo-DG27)was 270.4 μg/cm², which was about 4 times higher than that from theformulation without NaOH (65.3 μg/cm², #Diclo-DG25).

EXAMPLE 6

An in-vitro skin permeation study was conducted using four diclofenacsodium transdermal systems. The formulations used to prepare thesesystems are listed in Table 16, which include weight and weight percentof each ingredient in the formulations. The weight of sodium hydroxide(NaOH) was 0 g, 0.01 g, 0.02 g, and 0.05 g for formulation #Diclo-P64,-P86, -P65, and -P87 respectively. Each formulation was coated on arelease liner and dried in an oven at 55° C. for two hours to removewater and other solvents. The dried drug-in-adhesive/release liner filmwas laminated to a backing film. The backing/drug-in-adhesive/releaseliner laminate was then cut into round discs with a diameter of 11/16inch. The theoretical percent weight for each ingredient after drying(calculated assuming all the volatile ingredients were completelyremoved during drying) is listed in Table 17.

The in-vitro permeation of diclofenac sodium through human cadaver skinfrom these discs was performed using Franz-type diffusion cells with adiffusion area of 1 cm². The volume of receiver solution was 8 ml. Humancadaver skin was cut to desired size and placed on a flat surface withthe stratum corneum side facing up. The release liner was peeled awayfrom the disc laminate. The backing/drug-in-adhesive film was placed andpressed on the skin with the adhesive side facing the stratum corneum.The skin/adhesive/backing laminate was clamped between the donor andreceiver chambers of the diffusion cell with the skin side facing thereceiver solution. Twelve diffusion cells were used for eachformulation.

The cells were filled with 10% ethanol/90% water solution. At each timepoint, the pH at the interface between skin and the patch for threediffusion cells was measured by removing the receiving fluid, removingthe clamp and the donor chamber, gently teasing the patch away from theskin with tweezers, leaving the skin on the receiver chamber, measuringthe pH of the solution on the skin by placing the microelectrodedirectly onto the skin surface. The measured pHs at the skin/patchinterface were listed in Table 18. For all other cells, the receivingfluid was completely withdrawn and replaced with fresh ethanol/watersolution. The samples taken were analyzed by an HPLC for theconcentration of diclofenac sodium in the receiver solution. The pHs ofthe receiver solutions taken were measured by a pH meter. The cumulativeamount of diclofenac sodium across human cadaver skin was calculatedusing the measured diclofenac sodium concentrations in the receiversolutions, which were shown in Table 19. The pHs of the receiversolutions were listed in Table 20.

Since diclofenac sodium is not expected to react with NaOH, the NaOHconcentration listed in Table 2 equals the excess NaOH concentration.

The pH of the patch was determined using the following procedures. A 2.5cm² circular patch was punched out. Ten ml of purified water waspipetted into a glass vial, and a stir bar was added, the liner wasremoved from the patch and placed in the vial along with the patch. Thevial was then placed on a stir plate and the water/patch/liner mixturewas stirred for 5 minutes, at which point the liner was removed from thevial and discarded. The vial was again placed on a stir plate andstirring continued for an additional 18 hours. After 18 hours, the stirbar was removed from the vial and the pH of the solution determinedusing a calibrated pH meter. The measured pHs for the diclofenac sodiumtransdermal systems are listed in Table 21.

TABLE 16 Weight and Weight Percent of Each Ingredient Based on TotalSolution Weight for Four Diclofenac Sodium Transdermal Systems Diclo-P64Diclo-P86 Diclo-P65 Diclo-P87 Diclofenac sodium 0.6 g 0.6 g 0.9 g 0.6 g (9.2%)  (9.2%)  (9.2%)  (9.1%) Propylene glycol 0.9 g 0.9 g 0.9 g 0.9 g(13.8%) (13.8%) (13.8%) (13.6%) NaOH 0 0.01 g  0.02 g  0.05 g   (0.2%) (0.3%)  (0.8%) PIB adhesive (30% solid)   4 g   4 g   4 g   4 g (61.5%)(61.3%) (61.2%) (60.6%) Heptane   1 g   1 g   1 g   1 g (15.4%) (15.3%)(15.3%) (15.2%) DI water 0 0.01 g  0.02 g  0.05 g   (0.2%)  (0.3%) (0.8%)

TABLE 17 Weight and Theoretical Weight Percent of Each Ingredient in theDried Film for Four Diclofenac Sodium Transdermal Systems Diclo-P64Diclo-P86 Diclo-P65 Diclo-P87 Diclofenac sodium 0.6 g 0.6 g 0.9 g 0.6 g(22.2%) (22.1%) (22.1%) (21.8%) Propylene glycol 0.9 g 0.9 g 0.9 g 0.9 g(33.3%) (33.2%) (33.1%) (32.7%) NaOH 0 0.01 g  0.02 g  0.05 g   (0.4%) (0.7%)  (1.8%) PIB adhesive 1.2 g 1.2 g 1.2 g 1.2 g (44.4%) (44.3%)(44.1%) (43.6%)

TABLE 18 pHs at the Interface between Skin and Patch at Various TimePoints for Diclofenac Sodium Transdermal Systems Diclo-P64 Diclo-P86Diclo-P65 Diclo-P87  3 hours * 11.0 * 10.3  6 hours * 11.0 11.2  9.8 10hours 8.5 10.9 10.7 10.2 24 hours *  9.7 10.1  9.4 *Cannot be measuredbecause there was not enough solution at the interface

TABLE 19 Cumulative Amount of Diclofenac Sodium across human cadaverskin for Diclofenac Sodium Transdermal Systems (g/cm²) Diclo-P64Diclo-P86 Diclo-P65 Diclo-P87  3 hours  7.5  1.5  33.4  257.7  6 hours39.6 18.3 269.3  793.3 10 hours 63.2 49.3 654.4 1652.2 24 hours 34.6227.7  1733.8  3257.7

TABLE 20 pHs of Receiver Solutions at Various Time Points for DiclofenacSodium Transdermal Systems Diclo-P64 Diclo-P86 Diclo-P65 Diclo-P87  3hours 8.1 8.0 9.3 10.8  6 hours 7.4 7.9 7.7 10.0 10 hours 7.0 7.6 7.3 7.7 24 hours 7.0 8.9 7.5  9.6

TABLE 21 Excess NaOH Concentration and pH of Four Diclofenac SodiumTransdermal Systems Diclo-P64 Diclo-P86 Diclo-P65 Diclo-P87 Excess NaOH0 0.4 0.7 1.8 Concentration (wt %) pH 7.40 8.99 10.71 10.38

The cumulative amount of diclofenac sodium across human cadaver skin at24 hours increased from 34.6 g/cm² to 3257.7 g/cm² (Table 19) when thecalculated excess NaOH concentration in the dried patch was increasedfrom 0% to 1.8% (Table 17). The cumulative amount of diclofenac sodiumacross human cadaver skin at 24 hours from the system containing 0.4%NaOH (Diclo-P86) was 227.7 g/cm², which was about six times higher thanthat from the formulation without NaOH (34.6 g/cm2, #Diclo-P64). Thisresult indicated that the permeation of diclofenac sodium across humanskin could be enhanced by a NaOH concentration as low as 0.4%.

The pHs at the interface between skin and the patch were about the sameas shown in Table 18, even though the concentration of NaOH wasincreased from 0.4% to 1.8%. It was noticed that the less the amount ofsolution at the interface, the higher the NaOH concentration. It wasdifficult to measure the pH of interface between skin and patch for theformulations without NaOH or with a low NaOH concentration because therewas not enough solution on the top of the skin.

Since the pH measurement for the interface between skin and patch may bedifficult for low NaOH concentrations, the pHs of the receiver solutionswere measured at various time points. The pHs of receiver solutionslisted in Table 20 indicated that the pHs depend on the time intervalbetween sampling, the NaOH concentration in the patch, and the timepoint. The pHs at the 3-hour time point increased from 8 to 10.8 whenthe NaOH concentration in the patch was increased from 0.4% to 1.8%.

The pH of the diclofenac sodium patch measured using the procedureslisted above increased from 7.40 to 10.38 when the calculated excessNaOH concentration in the dried patch was increased from 0% to 1.8%(Table 21).

1. A composition of matter useful for the delivery of a nonsteroidalanti-inflammatory drug through a body surface, comprising a formulationcomprising: (a) a therapeutically effective amount of a nonsteroidalanti-inflammatory drug; (b) a hydroxide-releasing agent in an amounteffective to enhance the flux of the drug through the body surfacewithout causing damage thereto and effective to provide a pH in therange of approximately 8.0 to 13 at the body surface, during drugadministration; and wherein the amount of hydroxide-releasing agent inthe formulation is the total of (a) the amount required to neutralizeany acidic species in the formulation plus (b) an amount equal toapproximately 0.5 to 25.0 wt % of the formulation; and (c) apharmaceutically acceptable carrier suitable for topical or transdermaldrug administration, wherein: the composition is provided in atransdermal patch comprising a laminated structure that is to be affixedto the skin, the structure comprising a drug reservoir comprising theformulation contained within a polymeric matrix of a pharmaceuticallyacceptable adhesive material that serves to affix the system to the skinduring drug delivery, and wherein the hydroxide-releasing agentcomprises an inorganic hydroxide selected from the group consisting ofsodium hydroxide and potassium hydroxide.
 2. The composition of claim 1,wherein the pH at the body surface is in the range of approximately 8.0to 11.5.
 3. The composition of claim 2, wherein the pH at the bodysurface is in the range of approximately 8.5 to 11.5.
 4. The compositionof claim 1, wherein the carrier is aqueous.
 5. The composition of claim1, wherein the composition is free of additional permeation enhancers.6. The composition of claim 1, wherein the composition is free oforganic solvents.
 7. The composition of claim 1, wherein thehydroxide-releasing agent releases free hydroxide ions in the presenceof an aqueous fluid.
 8. The composition of claim 1, wherein the amountof inorganic hydroxide in the formulation is the total of (a) the amountrequired to neutralize any acidic species in the formulation plus (b) anamount equal to approximately 0.5 wt % to 4.0 wt % of the formulation.9. The composition of claim 1, wherein the drug is systemically acting.10. The composition of claim 1, wherein the drug is a propionic acidderivative.
 11. The composition of claim 10, wherein the propionic acidderivative is selected from the group consisting of ketoprofen,flurbiprofen, ibuprofen, naproxen, fenoprofen, benoxaprofen, indoprofen,pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen,butibufen, fenbufen, tiaprofenic acid, salts, esters, amides of any ofthe foregoing, and combinations thereof.
 12. The composition of claim11, wherein the propionic acid derivative is selected from the groupconsisting of ketoprofen and ibuprofen.
 13. The composition of claim 1,wherein the drug is selected from the group consisting ofacetylsalicylic acid, apazone, diclofenac, difenpiramide, diflunisal,etodolac, flufenamic acid, indomethacin, ketorolac, meclofenamate,mefenamic acid, nabumetone, phenylbutazone, piroxicam, salicylic acid,sulindac, tolmetin, salts, esters, amides of any of the foregoing, andcombinations thereof.
 14. The composition of claim 13, wherein the drugis selected from the group consisting of diclofenac, ketorolac, andpiroxicam.
 15. A system for the topical or transdermal administration ofa nonsteroidal anti inflammatory drug, comprising: (a) at least one drugreservoir containing the drug and a hydroxide-releasing agent in anamount effective to enhance the flux of the drug through the bodysurface without causing damage thereto and effective to provide a pH inthe range of approximately 8.0 to 13 at the body surface during drugadministration; and wherein the amount of hydroxide-releasing agent inthe reservoir is the total of (a) the amount required to neutralize anyacidic species in the reservoir plus (b) an amount equal toapproximately 0.5 to 25.0 wt % of the reservoir; (b) a means formaintaining the system in drug and enhancer transmitting relationship tothe body surface; and (c) a backing layer that serves as the outersurface of the system during use, wherein the drug reservoir iscomprised of a polymeric adhesive, wherein the hydroxide-releasing agentcomprises an inorganic hydroxide selected from the group consisting ofsodium hydroxide and potassium hydroxide.
 16. The system of claim 15,wherein the pH at the body surface is in the range of approximately 8.0to 11.5.
 17. The system of claim 16, wherein the pH at the body surfaceis in the range of approximately 8.5 to 11.5.
 18. The system of claim15, wherein the backing layer is occlusive.
 19. The system of claim 15,wherein the polymeric adhesive serves as the means for maintaining thesystem in drug and enhancer transmitting relationship to the bodyservice.
 20. The system of claim 15, wherein the drug is systemicallyacting.
 21. The system of claim 15, wherein the drug is a propionic acidderivative.
 22. The system of claim 21, wherein the propionic acidderivative is selected from the group consisting of ketoprofen,flurbiprofen, ibuprofen, naproxen, fenoprofen, benoxaprofen, indoprofen,pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen,butibufen, fenbufen, tiaprofenic acid, salts, esters, amides of any ofthe foregoing, and combinations thereof.
 23. The system of claim 22,wherein the propionic acid derivative is selected from the groupconsisting of ketoprofen and ibuprofen.
 24. The system of claim 15,wherein the drug is selected from the group consisting ofacetylsalicylic acid, apazone, diclofenac, difenpiramide, diflunisal,etodolac, flufenamic acid, indomethacin, ketorolac, meclofenamate,mefenamic acid, nabumetone, phenylbutazone, piroxicam, salicylic acid,sulindac, tolmetin, salts, esters, amides of any of the foregoing, andcombinations thereof.
 25. The system of claim 24, wherein the drug isselected from the group consisting of diclofenac, ketorolac, andpiroxicam.
 26. A composition according to claim 1 wherein the adhesivecomprises a pressure-sensitive adhesive (PSA) that is suitable forlong-term skin contact, and that is physically and chemically compatiblewith the active agent and hydroxide-releasing agent.
 27. A compositionaccording to claim 26 wherein the adhesive comprises polyisobutylene.28. A composition according to claim 26 wherein the patch is adapted todeliver the drug through a defined area of intact unbroken living skinor mucosal tissue having an area of about 20 cm² to about 60 cm².
 29. Acomposition according to claim 26 wherein the flux of the active agentthrough the body surface is increased relative to the rate that would beobtained in the absence of permeation enhancement, and the nonsteroidalanti-inflammatory drug permeates through the body surface of a patient,without causing damage thereto.
 30. A composition according to claim 29wherein the hydroxide-releasing agent represents about 0.5 wt % to 3.0wt % of the formulation, and the concentration of the active agent inthe formulation is between about 5 wt % to 20 wt % of the weight of thepolymeric matrix.
 31. A composition according to claim 30 wherein thepatch further comprises a flexible elastomeric backing layer thatfunctions as the primary structural element of the transdermal systemand provides the device with flexibility and occlusivity, the backinglayer being inert and incapable of absorbing drug, hydroxide-releasingagent, or components of the formulation contained within the device, andthat permits the device to follow the contours of the skin and be worncomfortably on areas of skin such as at joints or other points offlexure.
 32. A composition according to claim 31 wherein the backinglayer is formed from a synthetic polymer selected from the groupconsisting of polyester, polyethylene, polypropylene, polyurethane,polyvinylidine chloride, polyether amide, natural polymers, andmacroporous woven and nonwoven materials.
 33. A composition according toclaim 1 wherein the adhesive material comprises polyisobutylene.
 34. Acomposition according to claim 1 wherein the patch is adapted to deliverthe drug through a defined area of intact unbroken living skin ormucosal tissue having an area of about 20 cm² to about 60 cm².
 35. Acomposition according to claim 1 wherein the flux of the active agentthrough the body surface is increased relative to the rate that would beobtained in the absence of permeation enhancement, and the nonsteroidalanti-inflammatory drug permeates through the body surface of a patient,without causing damage thereto.
 36. A composition according to claim 1wherein the hydroxide-releasing agent represents about 0.5 wt % to 3.0wt % of the formulation, and the concentration of the active agent inthe formulation is between about 5 wt % to 20 wt % of the weight of thepolymeric matrix.
 37. A composition according to claim 1 wherein thepatch further comprises a flexible elastomeric backing layer.
 38. Acomposition according to claim 37 wherein the backing layer is formedfrom a synthetic polymer selected from the group consisting ofpolyester, polyethylene, polypropylene, polyurethane, polyvinylidinechloride, polyether amide, natural polymers, and macroporous woven andnonwoven materials.
 39. A system according to claim 15 wherein thepolymeric adhesive comprises polyisobutylene.
 40. A system according toclaim 15 wherein the patch is adapted to deliver the drug through adefined area of intact unbroken living skin or mucosal tissue having anarea of about 20 cm² to about 60 cm².
 41. A system according to claim 15wherein the flux of the active agent through the body surface isincreased relative to the rate that would be obtained in the absence ofpermeation enhancement, and the nonsteroidal anti-inflammatory drugpermeates through the body surface of a patient, without causing damagethereto.
 42. A system according to claim 15 wherein thehydroxide-releasing agent represents about 0.5 wt % to 3.0 wt % of theformulation, and the concentration of the active agent in theformulation is between about 5 wt % to 20 wt % of the weight of thepolymeric matrix.
 43. A system according to claim 15 wherein the patchfurther comprises a flexible elastomeric backing layer that functions asthe primary structural element of the transdermal system and providesthe device with flexibility and occlusivity, the backing layer beinginert and incapable of absorbing drug, hydroxide-releasing agent, orcomponents of the formulation contained within the device, and thatpermits the device to follow the contours of the skin and be worncomfortably on areas of skin such as at joints or other points offlexure.
 44. A system according to claim 15 wherein the backing layer isformed from a synthetic polymer selected from the group consisting ofpolyester, polyethylene, polypropylene, polyurethane, polyvinylidinechloride, and polyether amide, natural polymers, and macroporous wovenand nonwoven materials.